EP3317274A1 - Verwendung von chloroquin und clemizol-verbindungen zur behandlung von entzündungs-und krebserkrankungen - Google Patents

Verwendung von chloroquin und clemizol-verbindungen zur behandlung von entzündungs-und krebserkrankungen

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Publication number
EP3317274A1
EP3317274A1 EP16818845.6A EP16818845A EP3317274A1 EP 3317274 A1 EP3317274 A1 EP 3317274A1 EP 16818845 A EP16818845 A EP 16818845A EP 3317274 A1 EP3317274 A1 EP 3317274A1
Authority
EP
European Patent Office
Prior art keywords
subject
effective amount
inhibitor
administration
daily
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16818845.6A
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English (en)
French (fr)
Other versions
EP3317274A4 (de
Inventor
Jeffrey S. Glenn
Edward A. Pham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eiger Group International Inc
Original Assignee
Eiger Group International Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eiger Group International Inc filed Critical Eiger Group International Inc
Publication of EP3317274A1 publication Critical patent/EP3317274A1/de
Publication of EP3317274A4 publication Critical patent/EP3317274A4/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention is directed to the field of medicine and more specifically to the use of certain compounds for the treatment and prevention of inflammatory and cancerous conditions, especially in liver.
  • NASH non-alcoholic steatohepatitis
  • the present invention addresses these needs by providing methods for treatment and/or prevention of inflammatory and/or cancerous conditions as described below.
  • clemizole and or cholorquine or an analog thereof, to a subject in need thereof.
  • subjects are administered either R-chloroquine, clemizole or R- chloroquine in combination with clemizole.
  • the subject has an inflammatory condition.
  • the subject has an inflammatory liver condition.
  • the subject has non-alcoholic steatohepatitis, and wherein the method further comprises treating non-alcoholic steatohepatitss.
  • the method reduces lobular inflammation of the liver.
  • the method reduces the risk of liver cancer.
  • the subject has liver cancer, and wherein the method further comprises treating liver cancer.
  • clemizole and/or R-chloroquine is administered to a subject with non-alcoholic steatohepatitis.
  • the administration of clemizole or R-chloroquine to a subject results in reduced levels plasma alanine aminotransferase compared to vehicle controls.
  • the administration of clemizole and/or R- chloroquine to a subject results in a reduced non-alcoholic fatty liver disease activity score as determined by histological analyses of liver tissue.
  • the administration of clemizole and/or R-chloroquine results in reduced steatosis.
  • the administration of clemizole and/or R-chloroquine results in reduced hepatocyte ballooning.
  • the administration of clemizole and/or R-chloroquine results in reduced lobular inflammation.
  • clemizole and/or R-chloroquine is administered to a subject to reduce the risk of development of liver cancer.
  • the subject has been diagnosed with non-alcoholic steatohepatitis.
  • clemizole and/or R-chloroquine is administered to a subject suffering from liver cancer.
  • the administration of clemizole and/or R-chioroquine results in reduced tumor burden in the subject or increased survival of the subject.
  • clemizole 0.5-50 mg kg of clemizole is administered to a subject. In some aspects, clemizole is administered once daily, twice daily or thrice daily. In other aspects, clemizole is administered daily for 1, 2, 3, 4, 5, 6 or more weeks.
  • R-chloroquine 0.5-50 mg kg of R-chloroquine is administered to a subject.
  • R-chloroquine is administered once daily, every other day or weekly.
  • R-chioroquine is administered for 1,2,3,4,5,6 or more weeks.
  • R-chioroquine is administered as a double loading dose daily for the first two days of treatment, followed by a single dose which is half of the double loading dose for the remainder of the treatment.
  • FIG. 1 A scheme for the process of synthesis of R-chloroquine is illustrated.
  • Figure 2 The chemical structures of clemizole and ciemizole metabolites are shown.
  • Figure 3 illustrates the synthetic scheme for the good manufacturing practice (GMP) synthesis of clemizole.
  • Figure 5 The chemical structures of hydroxychloroquine (rac-1) and R- hydroxychloroquine is shown (R)-l .
  • Figure 6 A scheme for the process of synthesis of enantiomers of
  • FIG. 7 The chemical structures of hydroxychloroquine metabolites are shown.
  • Figure 8 Representative images of mouse livers depicting inhibition of tumor formation in mice treated with clemizole (compound D) are shown.
  • prophylacticaily effective amount as prophylaxis can be considered therapy.
  • dichloroquinoline is removed from the aqueous phase, and the remaining impurities is removed by further extraction between pi I 7 and pll 8, followed by charcoal treatment of the aqueous phase to remo ve a trace of highly-coloured material. Above pH 8 (the most convenient pH being around 12), pure hydroxychloroquine is extracted. Both (R)- l a and (S)-l a are oils, and require protection from light during storage, developing ayellow color otherwise. After purification, enantiomers (R)-la and (S)- la are converted to bis(dihydrogenphosphate) salts, ((R)-b and ((S)-lb), by treatment with phosphoric acid (two molar equivalents).
  • Methods for treatment of inflammatory conditions, steatohepatitis and inflammation associated liver cancer are also encompassed by the present invention.
  • Said methods of the invention include administering a therapeutically effective amount of clemizole and/or R- chloroquine to a subject in need thereof.
  • the present invention also provides methods for the treatment of an inflammatory condition, comprising administering to a subject one or more compounds or a composition comprising one or more compounds of the invention and a pharmaceutically acceptable vehicle.
  • the present invention also provides methods for the treatment or prevention of inflammatory conditions in combination with anti-inflammatory treatments presently utilized in the clinic.
  • antiinflammatory treatments include, but are not limited to, nonsteroidal anti-inflammatory drags such as, aspirin, ibuprofen and naproxen, corticosteroids, anti-inflammatory bioactive compounds such as, plumbagin or immune selective antiinflammatory derivatives.
  • the present invention provides methods for the treatment of non-alcoholic steatohepatitis comprising administering to a subject one or more compounds or a composition comprising one or more compounds of the invention and a pharmaceutically acceptable vehicle.
  • the term ''non-alcoholic steatohepatitis refers to liver diseases characterized by inflammation of the liver with concurrent fat accumulation in the liver.
  • the invention also provides methods for the treatment of non-alcoholic steatohepatitis in combination with treatments presently utilized in the clinic for the treatment of conditions commonly associated with non-alcoholic steatohepatitis, such as metabolic syndrome and/or diabetes mellitus.
  • treatments for metabolic syndrome and/or diabetes mellitus include, treatments to reduce insulin resistance, cholesterol and
  • triglycerides examples include but are not limited to, metformin, thiazolidinedione, pioghtazone and rosiglitazone.
  • treatments for hypercholesterolemia include, but are not limited to, statin, bile acid sequestrants, cholesterol absorption inhibitors, a fibric acid derivatives or nicotinic acid.
  • the present invention provides methods for the treatment or prevention of liver cancer, comprising administering to a subject one or more compounds or a composition comprising one or more compounds of the invention and a pharmaceutically acceptable vehicle.
  • liver cancer refers to hyperproliferative diseases of the liver, including, but not limited to, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, secondary or metastatic liver cancer and hepatoblastoma.
  • the present invention also provides methods for the treatment or prevention of liver cancer in combination with treatments presently utilized in the clinic for the treatment or prevention of liver cancer, including, but not limited to, chemotherapeutic agents.
  • compositions of the invention are provided.
  • clemizoie and R-chloroquine of the invention can be formulated in
  • compositions can comprise, in addition to clemizoie and/or R-chloroquine, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • carrier or oilier material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable H, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable H, isotonicity and stability.
  • Suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives can be included, as required.
  • the small molecule useful compound according to the present invention that is to be given to an individual, administration is preferably in a "therapeutically effective amount” or “prophylactically effective amount' '(as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration will depend on the nature and seventy of the condition being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
  • composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • NASH mice 100851 NASH was induced in 55 male mice by a single subcutaneous injection of 200 , ug streptozotocin (STZ, Sigrna-Aldrich, USA) solution 2 days after birth and feeding with high fat diet (HFD, 57 kcai% fat, cat#: HFD32, CLEA Japan, Inc., Japan) after 4 weeks of age. Mice that had been induced have NASH by this method are referred to below as NASH mice. 100861 Pharmaceutical compositions and route of drug administration
  • Compounds A, B, C, D and Vehicle were orally administered in a volume of 5 mL/kg.
  • Compound A comprised a recemic mixture of R-chloroquine and S-chloroquine.
  • Compound B comprised R-chloroquine.
  • Compound C comprised S-chloroquine.
  • Compound D comprised clemizole. All test compounds were weighed and dissolved in vehicle (5% DMSO/Water).
  • Compounds A, B, and C were orally administered at doses of 258 mg kg on the first 2 days and 129 mg/kg thereafter once daily.
  • Compound D was orally administered at doses of 89 mg/kg twice daily. Table 1 below summarizes the treatment schedule.
  • mice 100941 C57BL/6 mice (14-day -pregnant female) were obtained from Japan SIX, Inc.
  • Non-fasting blood was collected in polypropylene tubes with anticoagulant (Novo- hepann, Mochida Pharmaceutical, Japan) from submandibular bleeding at 6 (before dosing), 7 and 8 weeks of age. The collected blood samples were centrifuged and the supernatant were collected as heparinized plasma.
  • Non-fasting blood glucose in whole blood was measured using LIFE CHECK (E1D1A Co. Ltd., Japan).
  • Plasma ALT was measured by FUJI DRI-CHEM 7000 (Fujifilm Corporation, Japan).
  • HE staining sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie - Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (Wako Pure Chemical Industries). NAFLD Activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner DE. et al., Hepaiology, 2005;41: 1313). To visualize collagen deposition, Bouin's fixed liver sections were stained using picro-Sirius red solution (Waldeck, Germany).
  • EXAMPLE 2 Whole Blood biochemistry in mice administered with cloroquine or clemizole in NASH mice.
  • EXAMPLE 3 Reduced NAFLD activity score is observed in NASH mice treated with R-cloroquine or clemizole.
  • EXAMPLE 4 Liver fibrosis area is not affected by administration of test compounds in NASH mice.
  • Table 5 Fibrosis Area of livers of NASH mice administered with TEST compounds.
  • Sii us red-positive area (%) 1 .13 ⁇ 0.17 0.37 ⁇ 0.23 0.78 ⁇ 0.35 0.90 + 0.44 0.95 ⁇ 0.39
  • EXAMPLE 5 Body weight and Liver weight of mice with NASH-induced hepatocellular carcinoma administered with test compounds.
  • EXAMPLE 6 Administration of clemizole in mice with hepatocellular
  • carcinoma reduces liver tumor diameter and number of tumor nodules
  • EXAMPLE 7 Human patients with hepatocellular carcinoma (HCC) treated with clemizole.
  • a phase 11 a. open label pilot study is conducted to test the safety, tolerability, pharmacokinetic and pharmacodynamic activity of 200 mg vs. 400 mg vs. 500 mg clemizole hydrochloride given orally thrice daily, to subjects with hepatocellular carcinoma (HCC) that are either awaiting liver transplantation or have an unresectable lesion.
  • HCC hepatocellular carcinoma
  • the completed study treats up to 40 patients.
  • Initial clinical results from two patients with hepatocellular carcinoma who were administered 200 mg clemizole for 3 or 5 months are described below.
  • Patient #1 is a 70 year old man , diagnosed with HCC in the setting of chronic hepatitis B-induced cirrhosis. Diagnosis was determined by dynamic liver CT. Patient #1 had received radiofrequencey ablation treatment for HCC in 2011, but experienced progression of disease post-treatment. Patient #1 also received three courses of transarterial
  • TACE chemoembolization
  • Patient #2 is a 77 year old man, diagnosed with multifocal HCC in the setting of chronic hepatitis B-induced cirrhosis. Diagnosis was determined by dynamic liver magnetic resonance imaging. Patient #2 had failed and/or not tolerated sorafenib treatment and presented with disease progression post-treatment. Patient #2 then initiated clemizole treatment with oral administration of 200 mg clemizole thrice daily. After 5 months of clemizole treatment, the patient underwent follow up dynamic liver magnetic resonance imaging, and when a significant increase in tumor size would have been expected in the absence of any therapy, the HCC remained stable. At that time, the patient felt very well with no complaints or side effects.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Pain & Pain Management (AREA)
  • Virology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP16818845.6A 2015-06-30 2016-06-30 Verwendung von chloroquin und clemizol-verbindungen zur behandlung von entzündungs-und krebserkrankungen Pending EP3317274A4 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562187061P 2015-06-30 2015-06-30
PCT/US2016/040566 WO2017004454A1 (en) 2015-06-30 2016-06-30 Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions

Publications (2)

Publication Number Publication Date
EP3317274A1 true EP3317274A1 (de) 2018-05-09
EP3317274A4 EP3317274A4 (de) 2019-05-08

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Country Status (13)

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US (2) US10688083B2 (de)
EP (1) EP3317274A4 (de)
JP (2) JP7068827B2 (de)
KR (2) KR20230129590A (de)
CN (2) CN113274386A (de)
AU (3) AU2016288699B2 (de)
CA (2) CA2989634C (de)
HK (1) HK1249508A1 (de)
IL (4) IL300476B1 (de)
MX (3) MX2017016681A (de)
TW (3) TWI830262B (de)
WO (1) WO2017004454A1 (de)
ZA (1) ZA201708471B (de)

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